Loss of miR-204 Drives NPTX1-Dependent Mitochondrial Dysfunction and Neuronal Degeneration in Alzheimer's Disease

Alzheimer's disease (AD) is characterized by progressive cognitive decline accompanied by synaptic dysfunction and neuronal loss. Dysregulation of specific microRNAs (miRNAs) has been increasingly implicated in AD pathogenesis, suggesting that miRNA-mediated regulatory pathways may represent important mechanisms underlying neuronal vulnerability. Here, we identified mmu-microRNA-204-5p (miR-204) as a critical regulator of neuronal survival that is markedly downregulated in the hippocampus of 5xFAD mice. Through integrated bioinformatics analysis and experimental validation, we established neuronal pentraxin-1 (NPTX1) as a direct post-transcriptional target of miR-204. In primary cultured neurons, exposure to Aβ₁₋₄₂ oligomer (oAβ) drove marked upregulation of NPTX1 and precipitated neuronal injury, manifested by aberrant reactive oxygen species (ROS) accumulation, collapse of mitochondrial membrane potential, diminished cell viability, and dendritic degeneration. Inhibition of miR-204 further exacerbated these pathological changes and engaged mitochondrial apoptotic signaling, as evidenced by Bax upregulation, cytochrome c release, and caspase-3 cleavage. Conversely, restoration of miR-204 expression or genetic knockdown of NPTX1 attenuated oxidative stress, preserved mitochondrial integrity, and restored neuronal survival. Collectively, our findings uncover a previously unrecognized miR-204-NPTX1 regulatory axis that governs mitochondrial integrity and apoptotic susceptibility in AD, highlighting miR-204 as a potential therapeutic target for AD and related oxidative stress-associated neurodegenerative disorders.